EP1469859B1 - Verwendung von mehrfach ungesättigten Ketonen zur Behandlung der Psoriasis - Google Patents

Verwendung von mehrfach ungesättigten Ketonen zur Behandlung der Psoriasis Download PDF

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EP1469859B1
EP1469859B1 EP03704739A EP03704739A EP1469859B1 EP 1469859 B1 EP1469859 B1 EP 1469859B1 EP 03704739 A EP03704739 A EP 03704739A EP 03704739 A EP03704739 A EP 03704739A EP 1469859 B1 EP1469859 B1 EP 1469859B1
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group
compound
double bonds
psoriasis
hydrocarbon group
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French (fr)
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EP1469859A1 (de
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Berit DEPARTMENT OF BIOLOGY JOHANSEN
Marit DEPARTMENT OF BIOLOGY ANTHONSEN
Wenche Sjursen
Anne Kristen Holmeide
Lars Skattebol
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Coegin Pharma AS
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Avexxin AS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the use of certain polyunsaturated long-chain ketones for the treatment of psoriasis and in particular to ketones carrying electron withdrawing substituents alpha to the carbonyl functionality in such treatment.
  • Psoriasis is a common, chronic, inflammatory skin disorder.
  • Psoriatic tissue is characterised by chronic inflammation in both epidermis and dermis, the disease being further characterised by hyperplasia of epidermal keratinocytes, fibroblast activation, alteration of eicosanoid metabolism, and leukocyte infiltration.
  • PKA 2 phospholipase A 2
  • the phospholipases are a group of enzymes that release unsaturated fatty acids from the sn2 position of membrane phospholipids. Once released, the fatty acids are converted by various enzymes into biologically very important signalling molecules. Release of arachidonate initiates the arachidonate cascade leading to the synthesis of eicosanoids such as prostaglandins. Eicosanoids are important in a variety of physiological processes and play a central role in inflammation. In Inflammation, Vol. 18, No.1 1994, Andersen et al identify the presence of certain phospholipases in psoriatic human skin.
  • WO00/02561 the inventors describe a method for modifying vasoactivity by regulating a soluble A ⁇ -proinflammatory pathway.
  • the regulator is oleyloxyethylphosphorylcholine.
  • the present inventors have surprisingly found that compounds of somewhat similar structure or the same structure as those identified in the Perkin Transactions paper are selective for IVa PLA enzymes and are therefore ideal candidates for the treatment of psoriasis in the absence of side effects. Given that there are a total of 23 enzymes in the phospholipase group and each enzyme fulfils a different physiological and pathological function this is surprising. Moreover, the compounds of the invention have surprisingly been found to be particularly potent in reducing eicosanoid production, by for example, the inhibition of group IVa PLA 2 .
  • the invention provides a compound of formula (I) wherein R is a C 16-24 unsaturated hydrocarbon group interrupted ⁇ to the carbonyl group by a heteroatom or group of heteroatoms selected from S, O, N, SO, SO 2 said hydrocarbon group comprising at least 5 non-conjugated double bonds; and X is an electron withdrawing group selected from CHal 3 , CHHal 2 or CHalH 2 wherein
  • Hal represents a halogen for use in the manufacture of a medicament for the treatment of psoriasis.
  • the invention provides pharmaceutical composition
  • X is an electron withdrawing group selected from CHal 3 , CHHal 2 or CHalH 2 wherein Hal represents a halogen and a pharmaceutically acceptable excipient.
  • the group R preferably comprises 5 to 7 double bonds, preferably 5 or 6 double bonds, e. g. 5 double bonds which should be non-conjugated. It is also preferred if the double bonds do not conjugate with the carbonyl functionality.
  • the double bonds present in the group R may be in the cis or trans configuration however, it is preferred if the majority of the double bonds present (i.e. at least 50%) are in the cis configuration. In further advantageous embodiments all the double bonds in the group R are in the cis configuration or all double bonds are in the cis configuration except the double bond nearest the carbonyl group which may be in the trans configuration.
  • the group R may have between 16 and 24 carbon atoms.
  • the group R carries a heteroatom or group of heteroatoms positioned ⁇ , to the carbonyl.
  • the heteroatom is O or S or a sulphur derivative such as SO.
  • RCOX groups are those of formula selected from halo or C 1-6 -alkyl. If present the substituents are preferably non-polar, and small, e.g. a methyl group. It is preferred however, if the R group remains unsubstituted.
  • the group X is an electron withdrawing group, CHal 3 , CHal 2 H, CHalH 2 wherein Hal represents a halogen, e.g. fluorine, chlorine, bromine or iodine, preferably fluorine.
  • Hal represents a halogen, e.g. fluorine, chlorine, bromine or iodine, preferably fluorine.
  • the electron withdrawing group is CHal 3 , especially CF 3 .
  • Highly preferred compounds for use in the invention are EPASCOCF 3 and AKH 217 as depicted below.
  • Compounds of formula (I) may be manufactured using known chemical synthetic routes. It is convenient to begin synthesis from the commercially available compounds arachidonic acid, EPA or DHA. Conversion of the acid functionality of these compounds into, for example a -COCF 3 group can be achieved readily, e.g. by converting the carboxylic acid into its corresponding acid chloride and reacting the same with trifluoroacetic anhydride in the presence of pyridine.
  • the starting acid is reduced to an alcohol and, if required, converted to the corresponding thiol.
  • the nucleophilic thiol may then be reacted with a group such as BrCH 2 COCF 3 thereby introducing the carbonyl and electron withdrawing species.
  • Complete synthetic protocols may be found in J. Chem. Soc., Perkin Trans 1, 2000, 2271-2276 or J. Immunol., 1998, 161, 3421 .
  • the compounds of formula (I) may be formulated into medicaments using conventional techniques well known to the skilled pharmaceutical chemist.
  • the compounds may be formulated with well known excipients or pharmaceutical carriers.
  • the medicaments of the invention may also comprise other conventional additives such as antioxidants, preservatives, colouring, flavouring etc.
  • the medicaments of the invention may be formulated as tablets, pills, powder, capsules, emulsions but are preferably in the form of creams or ointments.
  • the mode of administration may be any known mode, such as oral, nasal, transmucosal, parenteral, topical, intradermal etc. However, it is advantageous if the medicament is applied topically, i.e. directly to the infected part of the human skin.
  • the amount of the medicament required to effect a successful treatment will, of course, depend on the patient and on the severity of the psoriasis. The dose will be readily determined by the skilled chemist.
  • the compounds of the invention may be used to treat psoriasis in combination with other known pharmaceuticals for said purpose and this forms a further aspect of the invention.
  • AACOCF 3 is from BIOMOL (Plymouth Meeting, PA, USA), and MAFP is from Cayman (Ann Arbor, MI, USA). All fatty acid compounds were stored under N 2 at -80°C.
  • the spontaneously immortalized human skin keratmocyte cell line HaCaT was kindly provided by Prof. N. E. Fusenig (Heidelberg, Germany). Cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) with 1 g glucose/l (Gibco BRL, Life Technologies Ltd, Paisley, Scotland), supplemented with 5% fetal calf serum (FCS) (HyClone Laboratories, Inc., Utah, USA), 0.3 mg/ml L-glutamine (Sigma Chemical Company, St.Louis, Mo, USA), 0.1 mg/ml gentamicine (Sigma) and 1 ⁇ g/ml fungizone (Gibco).
  • DMEM Dulbecco's Modified Eagle's Medium
  • FCS fetal calf serum
  • Confluent cells were stimulated with A 23187 , Il-1 ⁇ (10mg/ml) or TNF ⁇ (lomg/ml) in 0.5% (v/v) FCS for 1 hour before harvesting. Passages 40-80 of the cells were used.
  • Generation of HaCat transfectants expressing luciferase under strict control of transcription factor NF-kB is described elsewhere ( Anthonsen et al, J. Biol. Chem. 2001, 276, 30527 ).
  • the reporter plasmid pBIIX contains two copies of the HIV NF-kB sequence cloned upstream of the mouse fos promoter driving expression of the Photinus pyralis luciferase gene.
  • EIA detection was performed according to manufacturer description, Cayman Chemical, MI, USA. A dilution of 1:10 was used for PGE 2 measurement. Microplate Manager Software (Bio-Rad Laboratory) calculated sample data.
  • luciferase activities were determined using the Luciferase Reporter Assay system (Promega) and Turner Luminometer model TD-20/20 (Turner Designs) as described by the manufacturer.
  • Sources of IV PLA 2 enzyme activity were insect cells over expressing recombinant human IV PLA 2 (10 ⁇ g IV PLA 2 protein/ 10 6 cells; Bac PAK Baculovirus expression system; CLONTECH Laboratories, Palo Alto, CA, USA). Cytosolic fractions of insect cells were prepared as described in Schalkwijk et al (1992) Eur. J. Biochem. 210, 169-176 . The protein contents of the cytosolic fractions were measured with Bio-Rad protein assay (Bio-Rad Laboratories GmbH, Kunststoff, Germany) using bovine serum albumin as standard. The inhibitory derivatives were added 10 minutes prior to substrate addition. The preincubation of inhibitors was performed at room temperature.
  • TLC Thin layer chromatography
  • Confluent cells were labelled with 1 ⁇ Ci/ml [ 3 H] arachidonic acid in media supplemented with 0.5 % (v/v) FCS 24 hours before cell induction and inhibition. About 90 % of the radioactive arachidonic acid were incorporated in the cell membranes. Extracellular [ 3 H] arachidonic acid was removed by washing the cells 3 times in media. The HaCaT cells were then preincubated with inhibitor for 1 hour and stimulated with calcium ionophore for 1 hour. The cell media were collected and cleared by centrifugation.
  • Arachidonic acid and eicosanoids were extracted from media using Bond Elut C18 octadecyl columns (500 mg) (Varian SPP, Harbor City, CA) as described by Powell, Anal. Biochem. 164, 117-131, 1987 ; with modifications previously described Brekke, Cytokine, 4, 269-280, 1992 .
  • the samples were collected in glass tubes precoated with Sigmacoat.
  • the amount of PGE 2 in cell culture media from calcium ionophore stimulated HaCaT cells was measured using an enzyme immunoassay (EIA; Cayman).
  • EIA enzyme immunoassay
  • the assay is based on the competition between free PGE 2 and a PGE 2 -acetylcholinesterase for a limited amount of PGE 2 monoclonal antibody.
  • the media were diluted 1:10 before analyzing of the PGE 2 contents.
  • Microplate Manager Software Bio-Rad Laboratory
  • Confluent cells were pretreated with inhibitors in serum free medium for 1 hour, and then treated with stimulating agent for 1 hour.
  • Conversion of substrate [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] was measured as optical density at 580 nm after 4 hours according to Mosmann [ Mosmann T, J.Immunol. Methods 65, 55-63, 1983 ]. For each concentration of inhibitor nine parallels were measured.
  • EPASCOCF 3 and AKH-217 seem to have the same potency as IV PLA 2 inhibitors as AACOCF 3 (i.e. 75-80 % inhibition) ( Figure 1 ). MAFP and DHACOCF 3 were poorer IV PLA 2 inhibitors (50% and 30% inhibition respectively). The compound EPACH(OH)CF 3 was also tested which results in severe attenuation of inhibitory effect (10% inhibition). EPACOCH 3 was made as a control compound with methyl instead of the trifluoromethyl (CF 3 ) group. EPACOCH 3 showed no inhibition ( figure 1 ).
  • IC 50 values of EPASCOCF 3 and AACOCF 3 were measured to be 3.5 ⁇ 0 ⁇ M and 5.8 ⁇ 1.9 ⁇ M respectively ( Figure 2B ). While the IC 50 values of MAFP and EPACH(OH)CF 3 were determined to be 24 ⁇ 1.4 ⁇ M and 43 ⁇ 7.1 ⁇ M respectively ( Figure 2A ).
  • Concentrations higher than 10 ⁇ M of A 23187 were toxic as determined by MTT assay.
  • the next step in evaluating our synthetic fatty acid inhibitors was to examine their ability to reduce the extracellular release of PGE 2 in response to A 23187 in HaCaT cells. Before the cell experiments were performed, we evaluated the toxicity of the inhibitors. MTT assay showed that concentrations of 25 ⁇ M and higher of the fatty acid compounds are toxic to HaCaT cells (results not shown).
  • HaCat cells upregulate expression of cyclooxygenase 2 message when treated with LPS (200 ng/ml, 5% human serum) for 30 min. (unpublished results). Upon ionophore stimulation for one hour, PGE 2 accumulates in medium ( Figure 3B ).
  • HaCaT cells were stimulated with the proinflammatory cytokines IL-1 ⁇ or TNF ⁇ .
  • cytokines IL-1 ⁇ or TNF ⁇ As a measure of inflammation, activation of the transcription factor NF-kB was analysed.
  • TNF ⁇ or IL-1 ⁇ activates NF-kB in HaCat cells ( Tansen et al, J. Immunol., 1998, 161, 3421 ).
  • NF-kB activation was analysed as luciferase expression.
  • Treatment of the stably transfected HaCat-pBIIX cells with TNF ⁇ or IL-1 ⁇ . for 1 h enhanced NF-kB-dependent expression (not shown).
  • IL-1 ⁇ stimulated luciferase expression was dose-dependently inhibited by 81%.
  • TNF ⁇ stimulated NF-kB activation was inhibited does-dependently AKH217 by 91% ( Figure 4 ) thus confirming that our synthetic fatty acid inhibitors may be useful in inhibiting inflammatory responses.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Claims (12)

  1. Verbindung der Formel (I)
    Figure imgb0020
     wobei R eine ungesättigte C16-24-Kohlenwasserstoffgruppe ist, die in β-Richtung zur Carbonylgruppe durch ein Heteroatom oder eine Gruppe von Heteroatomen unterbrochen ist, das bzw. die aus S, O, N, SO, SO2 ausgewählt ist bzw. sind, wobei die Kohlenwasserstoffgruppe wenigstens 5 nichtkonjugierte Doppelbindungen aufweist; und
    X ein elektronenentziehende Gruppe ist, die aus CHal3, CHHal2 oder CHalH2 ausgewählt ist, wobei Hal ein Halogen darstellt, zur Verwendung bei der Herstellung eines Medikaments zur Behandlung von Psoriasis bzw. Schuppenflechte.
  2. Verbindung zur Verwendung nach Anspruch 1, wobei die Kohlenwasserstoffgruppe 5 bis 7 Doppelbindungen aufweist.
  3. Verbindung zur Verwendung nach Anspruch 2, wobei die Kohlenwasserstoffgruppe 5 Doppelbindungen aufweist.
  4. Verbindung zur Verwendung nach einem der Ansprüche 1 bis 3, wobei keine Doppelbindung mit der Carbonylgruppe konjugiert ist.
  5. Verbindung zur Verwendung nach einem der Ansprüche 1 bis 4, wobei alle Doppelbindungen sich in der cis-Konfiguration befinden.
  6. Verbindung zur Verwendung nach einem der Ansprüche 1 bis 4, wobei alle Doppelbindungen sich in der cis-Konfiguration befinden, mit Ausnahme der Doppelbindung, die dem Carbonyl am nächsten liegt.
  7. Verbindung zur Verwendung nach einem der Ansprüche 1 bis 6, wobei die R-Gruppe 19 bis 21 Kohlenstoffatome aufweist.
  8. Verbindung zur Verwendung nach einem der Ansprüche 1 bis 7, wobei das Heteroatom oder die Gruppe von Heteroatomen O, S oder SO ist bzw. sind.
  9. Verbindung zur Verwendung nach einem der Ansprüche 1 bis 8, wobei die RCOX-Gruppe eine der folgenden ist:
    Figure imgb0021
    Figure imgb0022
    Figure imgb0023
    Figure imgb0024
  10. Verbindung zur Verwendung nach einem der Ansprüche 1 bis 9, wobei X CHal3 ist.
  11. Verbindung zur Verwendung nach Anspruch 1, wobei RCOX
    Figure imgb0025
     oder
    Figure imgb0026
     ist.
  12. Pharmazeutische Zusammensetzung mit einer Verbindung der Formel (I)
    Figure imgb0027
     wobei R eine ungesättigte C16-24-Kohlenwasserstoffgruppe ist, die in β-Richtung der Carbonylgruppe durch ein Heteroatom oder eine Gruppe von Heteroatomen unterbrochen ist, das bzw. die aus S, O, N, SO, SO2 ausgewählt ist bzw. sind, wobei die Kohlenwasserstoffgruppe wenigstens 5 nichtkonjugierte Doppelbindungen aufweist und X eine elektronenentziehende Gruppe darstellt, die aus CHal3, CHHal2 oder CHalH2 ausgewählt ist, wobei Hal ein Halogen darstellt, und einem pharmazeutisch verträglichen Excipienten bzw. Arzneiträger.
EP03704739A 2002-01-29 2003-01-29 Verwendung von mehrfach ungesättigten Ketonen zur Behandlung der Psoriasis Expired - Lifetime EP1469859B1 (de)

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GBGB0202002.2A GB0202002D0 (en) 2002-01-29 2002-01-29 Use
GB0202002 2002-01-29
PCT/GB2003/000364 WO2003063878A1 (en) 2002-01-29 2003-01-29 Use of polyunsaturated ketones for the treatment of psoriasis

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EP2248798A1 (de) * 2009-05-08 2010-11-10 Pronova BioPharma Norge AS Neue Lipidverbindungen
GB0909643D0 (en) * 2009-06-04 2009-07-22 Avexxin As Glomerulonephritis treatment
JP6012468B2 (ja) * 2009-10-02 2016-10-25 アヴェクシン エーエス 抗炎症性２−オキソチアゾールおよび２−オキソオキサゾール
GB201014633D0 (en) * 2010-09-02 2010-10-13 Avexxin As Rheumatoid arthritis treatment
NZ610705A (en) 2010-11-05 2014-10-31 Pronova Biopharma Norge As Methods of treatment using lipid compounds
GB201205394D0 (en) 2012-03-27 2012-05-09 Adlens Ltd Improvements in or relating to deformable non-round membrane assemblies
GB201221329D0 (en) * 2012-11-27 2013-01-09 Avexxin As Dermatitis treatment
CN105102438B (zh) 2013-01-29 2019-04-30 埃维克辛公司 抗炎症和抗肿瘤的2-氧代噻唑类和2-氧代噻吩类化合物
AU2014222389B2 (en) 2013-02-28 2018-11-29 Pronova Biopharma Norge As A composition comprising a lipid compound, a triglyceride, and a surfactant, and methods of using the same
GB201313238D0 (en) 2013-07-24 2013-09-04 Avexxin As Process for the preparation of a polyunsaturated ketone compound
GB201409363D0 (en) * 2014-05-27 2014-07-09 Avexxin As Skin cancer treatment
GB201413695D0 (en) 2014-08-01 2014-09-17 Avexxin As Compound
GB201501144D0 (en) 2015-01-23 2015-03-11 Avexxin As Process for the preparation of a polyunsaturated ketone compound
US20180104201A1 (en) 2015-04-28 2018-04-19 Pronova Biopharma Norge As Use of structurally enhanced fatty acids containing sulphur for preventing and or treating non alcoholic steatohepatitis
GB201604318D0 (en) 2016-03-14 2016-04-27 Avexxin As Combination therapy
GB201604316D0 (en) 2016-03-14 2016-04-27 Avexxin As Combination therapy
KR20190015320A (ko) * 2016-06-03 2019-02-13 아벡신 에이에스 다중불포화 케톤 및 코르티코스테로이드를 포함하는 조합 치료요법
CA3025696A1 (en) * 2016-06-03 2017-12-07 Avexxin As Combination therapy comprising a polyunsaturated ketone and a secosteroid
GB201609735D0 (en) * 2016-06-03 2016-07-20 Avexxin As Combination therapy
CA3025698A1 (en) * 2016-06-03 2017-12-07 Avexxin As Combination therapy comprising a polyunsaturated ketone and a calcineurin inhibitor
CN109789111B (zh) * 2016-09-21 2021-11-16 埃维克辛公司 药物组合物
EP3638221B1 (de) * 2017-06-16 2021-09-29 Avexxin AS Zusammensetzungen und verfahren zur behandlung von fibrotischen erkrankungen
PT3720431T (pt) 2017-12-06 2024-12-05 Basf As Derivados de ácidos gordos para o tratamento da esteato-hepatite não alcoólica
GB201807892D0 (en) 2018-05-15 2018-06-27 Avexxin As Processes in the preparation of polyunsaturated ketone compounds
GB202020843D0 (en) 2020-12-31 2021-02-17 Coegin Pharma Ab Actinic keratosis treatment

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JPH11199493A (ja) * 1997-11-13 1999-07-27 Nof Corp 皮膚外用剤組成物
AU4994899A (en) 1998-07-13 2000-02-01 University Of South Florida Modulation of the phospholipase a2 pathway as a therapeutic
US20020165119A1 (en) 2001-01-31 2002-11-07 Alan Leff Method of treating inflammatory conditions by inhibiting cytosolic phospholipase A2
EP1243524A3 (de) * 2001-03-16 2004-04-07 Pfizer Products Inc. Pharmazeutisches Kit fÜr sauerstoffempfindliche Medikamente
US20040111957A1 (en) * 2002-12-13 2004-06-17 Filippini Brian B. Water blended fuel composition

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JP2005518419A (ja) 2005-06-23
KR20040089127A (ko) 2004-10-20
DK1469859T3 (da) 2012-03-19
JP4608214B2 (ja) 2011-01-12
GB0202002D0 (en) 2002-03-13
US20150202165A1 (en) 2015-07-23
NO334413B1 (no) 2014-02-24
US20100152293A1 (en) 2010-06-17
EP1469859A1 (de) 2004-10-27
KR100874505B1 (ko) 2008-12-18
PT1469859E (pt) 2012-03-06
NO20043548L (no) 2004-08-25
CA2473687C (en) 2011-04-12
ATE535245T1 (de) 2011-12-15
CN1678323A (zh) 2005-10-05
ES2378303T3 (es) 2012-04-11
US8524776B2 (en) 2013-09-03
CN101849929A (zh) 2010-10-06
US20050165116A1 (en) 2005-07-28
US9375409B2 (en) 2016-06-28
US20130324613A1 (en) 2013-12-05
WO2003063878A1 (en) 2003-08-07

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